Lecture 16: Secretions of the GI tract and Pancreas Flashcards
What is the function of saliva?
- Initial digestion of Starches and lipids
- Dilution and buffering of ingested food
- Lubrication of ingested food w/ mucus
What are Parotid glands?
- Composed of serous cells
- Secrete fluids composed of water, ions, enzymes (rich in amylase)
- Secrete 25% of the daily output of saliva
What are submaxillary and Sublingual glands?
- Composed of serous and mucous cells
- Secrete aqueous fluid and mucin glycoprotein for lubrication
- Secrete majority, 75%, of daily output of saliva
Describe the structure/function of a salivary gland (acinus, myoepithelial cells, intercalated duct, and striated ducts)
Acinus (blind end) - acinar cells secrete initial saliva
Myoepithelial cells - motile extensions, when stimulated by neural input, contract to eject saliva into the mouth
Intercalated duct - saliva here is similar in ionic composition to plasma
Striated duct - modify the initial saliva to produce the final saliva (hypotonic), alter the concentration of various electrolytes
What is saliva composed of?
H2O, electrolytes, α-amylase, lingual lipase, kallikrein, and mucus
What are the concentrations of electrolytes that make saliva hypotonic compared to plasma?
Increased K+ & HCO3 concentrations
Decreased Na+ & Cl- concentrations
What are the 2 main steps in the formation of saliva and the cells involved?
1) Formation of isotonoc, plasma-like, solution by acinar cells
2) Modification of the isotonic solution by the ductal cells
What are the transport mechanism occuring on the lumen/apical side of the salivary ductal cell?
Na+/H+ exchanger
Cl-/HCO3- exchanger
H+/K+ exchanger
What are the transport mechanism occurs on the blood/basolateral side of the salivary ductal cell?
- Na+/K+ ATPase
- Cl- channels
- HCO3-/Na+ symporter
During salivary secretion what is the combined action of solute movement and what is the net effect; why does it become hypotonic?
- Absorption of Na+ and Cl- (lower compared to plasma)
- Secretion of K+ and HCO3- (higher compared to plasma)
- Net absorbtion of solute (more NaCl is absorbed than KHCO3 secreted), and because ductal cells are impermeable to water the solution can become hypotonic
How does saliva become hypotonic as it flows through the ducts?
Ductal cells are impermeable to H2O
Discuss the ANS innervations of salivary glands, which is the dominant effect; why is this one of our exceptions?
PNS - presynaptic nerves originate at facial (CN VII) and glossopharyngeal (CN IX) nerves - PNS is DOMINANT effect
SNS - preganglionic nerves originate at the cervical ganglion, whose postganglionic fibers extend to gands in the periarterial space
*BOTH PNS and SNS stimulate salivary secretion - one of the exceptions
What stimulants activate and inhibit the PNS for salivary secretion, describe the pathway?
- Conditioning, food, nausea, smell (activators)
- Dehydration, fear, and sleep (inhibitors)
- Presynaptic nerves of CN VII or IX will release ACh that binds to a mAChR –> Increases IP3 and Ca2+ in the acinar or ductal cells, which will increase the secretion of saliva
Decribe the SNS innervation pathway for secretion of saliva
- Pre-ganglionic nerves from T1-T3 synapse at cervical ganglion.
- Post-ganglionic sympathetic neurons release NE, which interacts w/ β-adrenergic receptors on acinar and ductal cells.
- Activation of these receptors leads to stimulation of adenyly cyclase and production of cAMP, which leads to increased saliva production
Stimulation of salivary cells results in what 3 things?
- Increased saliva production
- Increased HCO3 and enzyme secretion
- Contraction of myoepithelial cells
What effects do Vasopressin and aldosterone have on the composition of saliva?
Modify composition by decreasing its [Na+] and increasing its [K+]
What are the 2 unusual features in the regulation of salivary secretion?
- Salivary is exclusively under the control of the ANS
- Salivary secretion is increased by BOTH the PNS and SNS (generally these 2 have opposite actions in the GI tract)
What are the main components secreted in gastric juice?
- HCL (H+)
- Pepsinogen
- Mucus
- Intrinsic factor
- H2O
What is the function of HCL (H+) in gastric juice?
- Together w/ pepsin, it initiates protein digestion
- Necessary for conversion of pepsinogen to pepsin
- Kills a large # of bacteria that enter the stomach
Function of the mucus secreted in gastric juice?
- Lines the wall of stomach and protects it from damage
- Lubricant
- Together w/ HCO3, it neutralizes acid and maintains the surface of mucosa at neutral pH
Function of Intrinsic Factor (IF) secreted in gastric juice?
Required for the absorption of vitamin B12 in the ileum
What are the 2 gland divisions of the gastric mucosa, where is each found, and what is the function of each?
Oxyntic gland - proximal 80% of stomach (body and fundus), secretes acid
Pylroic gland - distal 20% of stomach (antrum), synthesizes and releases gastrin
What cells types are found in the oxyntic gland and what does each secrete?
- Mucous neck cell: mucus and pepsinogen
- Parietal cells: HCL and IF
- Enterochromaffin-like cell: Histamine
- D cell: Somatostatin
- Chief cell: Pepsinogen
- Enterochromaffin cell (ANP): Serotonin
What cell types are found in the pyloric gland and what does each secrete?
- Mucous neck cell: mucus and pepsinogen
- G cell: gastrin
- D cell: somatostatin
What does the # of parietal cells determine?
Maximal secretory rate
What is the function of the low gastric pH (1-2) and where is HCL formed?
- Low pH converts pepsinogen to pepsin
- HCL is formed at the villus-like membranes of the canaliculi
Atropine blocks what component of the ANS during salivarys secretion?
Blocks ACh binding to mAChR
Discuss the cellular mechanism of HCL secretion by gastric parietal cells
- CO2 + H2O inside cells are converted to H2CO3 by carbonic anhydrase, which is then quickly converted to H+ and HCO3-
- On the luminal/apical side: there is a K+/H+ ATPase, which moves H+ into the lumen and Cl- will follow H+ to form HCL
- On the basolateral/blood side: there is an Na+/K+ ATPase moving Na+ out and K+ into the cell. There is also a HCO3/Cl- exchanger that moves Cl- into the cell and HCO3- out.
What effect does Omeprazole have on gastric parietal cells; used in the treatment of?
- Inhibits the K+/H+ ATPase so that less H+ is secreted into the lumen which ultimately decreases HCL
- Used in the treatment of ulcers
What is the net effect of the cellular mechanism of gastric parietal cells?
Net secretion of HCL and net absorption of HCO3-
What is Alkaline tide?
This occurs after a meal where during the production of HCL by parietal cells more HCO3- is entering the blood and raising the pH
What are the agents that stimulate H+ secretion by gastric parietal cells?
Vagus n releases ACh to an mAChR –> Gq –> IP3/Ca2+
G cells release gastrin to CCKβ receptor –> Gq –> IP3/Ca2+
ECL cells release Histamin to H2 receptor –> Gs –> cAMP
*These pathways all lead to activation of H+/K+ ATPase and the secretion of H+
What are the agents that inhibit H+ secretion by gastric parietal cells?
- Somatostatin and Prostaglandins –> Gi —> inhibit cAMP
- Somatostatin can also inhibit ECL cells and G cells
- Prostaglandins can inhibit ECL cells
What effect does Cimetidine have on the secretion of H+ by gastric parietal cells and what is it used to treat?
- Antagonst of H2 receptors, which block histamines action
- Used to treat duodenal/gastric ulcers, and GERD
Why are prostaglandins important within the stomach and what effect does NSAIDs have on them?
- Protect the lining of the GI by decreasing gastric acid production, decreasing blood flow, and producing mucous
- NSAIDs will inhibit the actions of Prostaglandins
What is the passive feedback mechanism for regulatng HCL secretion?
As the pH falls, gastrin release is inhibited, which will decrease the amount of HCL secreted
Discuss how the role of the vagus nerve on HCL secretion from parietal cells is twofold; how does Atropine play a role here?
- There is a direct and indirect pathway of vagus nerve stimulation
- Direct: release of ACh to parietal cells (Atropine can block ACh)
- Indirect: GRP is released from vagus to G cells, which increases gastrin secretion (Atopine will NOT block the vagal affects on gastrin secretion due to the NT being GRP)
How is the rate of HCL secretion potentiated by histamine, ACh, and gastrin?
- Histamine potentiates the action sof ACh and gastrin
- ACh potentiates the actions of histamine and gastrin
*Potentiation is a combined response to 2 stimulants, which exceed the sum of their individual responses
What are the pharmological implications due to the potentiation effect produced by histamine, ACh, and gastrin?
- Antagonists of H2 receptors (i.e., Cimetidine) block the direct action of histamine and also block potentiated effects of ACh and gastrin
- Antagonist of mAChRs (i.e., Atropine) blocl the direct effects of ACh and the ACh-potentiated effects of histamine and gastrin
What are the 3 phases of gastric HCL secretion?
- Cephalic phase (30% total HCL secreted): via vagus
- Gastric phase (60% total HCL secreted): local nervous secretory reflexes, vagal reflexes, and gastrin-histamine stimulation
- Intestinal phase (10% total HCL secreted) - nervous mechanisms and hormonal mechanisms
What are the stimuli and mechanism for the cephalic phase of gasrtic HCL secretion; what is the effect of vagotomy on this phase?
Stimuli: smelling, tasting, chewing, swallowing, and conditioning
- Mechanisms:
- Vagus releases ACh to parietal cell = HCL secretion
- Vagus releases GRP to G cells = gastrin secretion, which is delivered back to the stomach to stimulate HCL secretion from parietal cells
*Vagotomy abolishes this phase*
What are the stimuli for the gastric phase of gastric HCL secretions
Stimuli: distention of stomach and presence of broken down proteins, AA’s and small peptides
What are the mechanisms involved in the gastric phase of gastric HCL secretion (4 of them)?
Mechanisms: Distention activates mechanoreceptors in the mucosa of oxyntic and pyloric glands
- Vagus nerve releases ACh to parietal cells = stimulates HCL secretion
- Vagus nerve releases GRP to G cells = secretion of gastrin, which travels to parietal cells and stimulates HCL secretion
- Distention of antrum causes local pyloropyloric reflex –> gastrin –> parietal cells
- AA’s and small peptides causes gastrin release to parietal cells
What effect does coffee (caffeinated and decaffeinated) have on gastric HCL secretion?
Stimulates gastric HCL secretion
What leads to the HCL secretion during the intestinal phase?
- Distention of small intestine stimulates acid secretion
- Digested protein stimulates acid secretion via direct effect on parietal cell: gastrin (intestinal G cells) –> parietal cell
What is the non-parietal component of gastric juice composed of?
- Basal alkaline secretion of constant and low volume
- Primarly Na+, Cl+ and K+ at same concentration as plasma
- HCO3 is secreted at a concentration of ~30 mEq/L
Waht is the parietal component of gastric juice composed of?
- Slightly hyperosmotic
- Contains 150-160 mEq H+/L and 10-20 mEq K+/L
- Cl- is the only anion present
- As the secretion rate increases, the concentration of electrolytes begins to approach those of pure parietal juices
How is the release of gastrin regulated by somatostatin, gastrin, H+ and vagus stimulation?
- Somatostatin acts on G cells to inhibit gastrin release
- Vagal activation stimulates gastrin release through GRP and inhbits the release of somatostatin
- Negative feedback by gastrin causes increased somatostatin
- H+ in gastric lumen stimulates the release of somatostatin
What is the most important stimuli for pepsinogen release, where is it released from, and what is the pH requirement?
- Secreted by Chief and Mucus cells in the oxyntic glands
- Requires H+ secretion from parietal cells to lower pH <5
- Vagus is the most important stimulus
- H+ triggers local cholinergic reflexes that stimulate chief cells to secrete pepsinogen
What effect does pepsin have on pepsinogen?
Pepsin converts more pepinogen to pepsin
What is the function of pepsin and what is its optimal pH, when is it reversibl activated, and irreversibly activated?
- Proteolytic enzyme, splits interior peptide linkages
- Optimal pH: 1.8 -5.5
- Reversibly inactivated: pH >5.0
- Irreversibly inactivated: pH >7-8
What is intrinsic factor and why is it so important?
- Mucoprotein secreted by parietal cells
- Binds to and protects B12 for absorption in the Ileum
- ONLY secretion by the stomach that is required (essential)
What does failure to secrete IF by parietal cells lead to?
- Pernicious anemia
What are common underlying causes of pernicious anemia?
- Atrophic gastritis: chronic inflammation of the stomach mucosa that leads to loss of parietal cells
- Autoimmune metaplastic atrophic gastritis: immune system attacks IF protein or gastric parietal cells
How does the gastric mucosal barrier protect the gastric mucosal epithelium against the HCL and pepsin?
- Mucous neck cells secrete mucus
- Gastric epithelial cells secrete HCO3
What substances protect the gastric mucosa?
Mucous, HCO3, prostaglandins (i.e., Misoprostol), mucosal blood flow, gastrin, and growth factors
What substances damage the gastric mucosa?
Acid, pepsin, NSAIDs, H. pylori, alcohol, smoking, bile, and stress
What is Zollinger-Ellison syndrome, causes, and mechanism of the disease?
- Tumor, usually in the pancreas, secretes large quanities of gastrin, which increases H+ secretion by parietal cells and increases parietal cell mass (trophic effect)
- Excessvie H+ arrives to duodenum and overwhelms the buffer capacity of HCO3, creating an ulcer
- Low duodenal pH inactivates pancreatic lipase –> steatorrhea
What is the Secretin stimulation test?
- Used in the dx of gastrin-secreting tumors (i.e., Zollinger-Ellison)
- Under normal conditions, secretin administration inhibits gastrin release
- In gastrinomas, injection of secretin causes a paradoxical increase in gastrin release
What are the predominate causes of peptic ulcer disease, and what are the two types?
- H. pylori infection and the use of NSAIDs
- Gastric and duodenal ulcers
How is H. pylori able to damage the gastric mucosa; what is a common diagnostic test based on?
- Releases cytotoxins that break down the barrier and underlying cells
- Release urease which converts urea –> NH3, which alkalinizes the local enviornment. The NH3 reacts w/ H+ –> NH4+ (ammonium).
- Common diagnostic test based on urease activity
Where do gastric ulcers form, major cause, and how do they differ from duodenal ulcers?
- Form on lining of stomach
- Gastric mucosal barrier is defective, as opposed to increased H+ secretion seen in duodenal ulcers
- Major causative agent = H. pylori
Where do duodenal ulcers form, major cause, and difference from gastric ulcers?
- Form on lining of the duodenum
- More common than gastric ulcers and H+ secretion rates are higher than normal
- H. pylori is a major etiologic factor
What are the secretory cells of the exocrine pancreas and what does each secrete?
- Acinus: lined by acinar cells that secrete enzymes
- Ducts: lined by ductal epithelial cells; extends to the region in the acinus containing centroacinar cells. Ductal and centroacinar cells secrete the aqueous solution containing HCO3
What are the enzymes secreted by acinar cells of the pancreas?
- Amylases and lipases are secreted as active enzymes
- Proteases are secreted in inactive forms and converted to their active forms in the lumen of the duodenum
What is produced by pancreatic centroacinar and ductal cells; what happens to the initial secretion?
- Produce initial aqueous solution which is isotonic and contains Na+, K+, Cl-, and HCO3-
- Initial secretion is modified by transport processes in the ductal epithelial cells
What are the transport mechanism inside the pancreatic ductal cell, on the luminal/apical side, and on the basolateral/blood side?
- Inside ductal cell CO2 + H2O is converted to H2CO3 by carbonic anhydrase, which quickly dissociates into HCO3 and H+
- Luminal side: HCO3 is sent to lumen in exhchange for Cl-
- Basolateral side: Na+/K+ ATPase brings K+ in and a Na+/H+ exhanger gets H+ out of the cell into the blood
*Na+ is free to travel between pancreatic ductal cells to be used by the Na+/H+ exchanger
What is the net result of tranport mechanisms by the pancreatic ductal cells?
Secretion of HCO3 into pancreatic ductal juice and net absorption of H+ into blood
How does cystic fibrosis affect the pancreas?
- One of the 1st organs to fail in CF patients
- Mutations in the CFTR, a regulated Cl- channel in the apical surface of the duct cells, leads to a decrease in HCO3 secretion
- Pancreas loses ability to flush active enzymes out of the duct
- May lead to recurrent acute and chronic pancreatitis
What is the cephalic phase of pancreatic secretion, stimuli, mediated by, and what does it produce?
Stimuli: smell, taste, and conditioning
Mediated: by Vagus nerve
Produces: mainy an enzymatic secretion
What is the gastric phase of pancreatic secretion, stimuli, mediated by, and what does it produce?
Stimuli: distention of stomach
Mediated: by Vagus nerve
Produces: mainly an enzymatic secretion
The intestinal phase of pancreatic secreton accounts for what percentage of the pancreatic secretion and what does it produce?
- Accounts for 80% of pancreatic secretion
- Enzymatic and aqueous secretions are stimulated
How does the SNS innervate the pancreas and what are its effects?
- Post-ganglionic nerves from celiac and superior mesenteric plexus
- Inhibits secretions
How does the PNS innervate the pancreas and what are its effects?
- Pre-ganglionic fibers synapse in the ENS
- Post-ganglionic fibers synapse on the exocrine pancreas
- Stimulates pancreatic secretions
Explain why CCK is an important hormonal regulator of pancreatic secretion during the intestinal phase, what stimulates it, where is it released from, and what potentiates its effect?
- Phe, Met, Trp, small peptides, and FA’s stimulate I-cells of the duodenum to release CCK.
- CCK leads to the contraction of the gallbladder and release of the enzymatic secretion from the pancreas into the duodenum
- ACh can potentiate this effect
Explain why Secretin is an important hormonal regulator of pancreatic secretions during the intestinal phase, where is it released from, what stimulates it, and what potentiates its effects?
- H+ stimulates S cells of the duodenum to release Secretin, which acts on ductal cell increasing their release of the aqueous secretion containing Na+ and HCO3
- ACh and CCK potentiate the effects of Secretin
